Description: The potential for widespread dissemination of lethal poxviruses such as smallpox during bioterrorism has led to renewed scientific efforts to understand the pathogenesis of this virus and related orthopoxviruses. Poxviruses have evolved many strategies to modulate and evade host immunity, compromising viral recognition and clearance by the host as well as the development of long-lasting immune responses. Vaccinia virus has been widely used as an infectious vaccine agent to induce immunity against smallpox. However, concerns related to the effectiveness of vaccinia-induced immunity, as well as complications associated with vaccinia virus immunization in the current populace, have lead to a call for development of improved poxvirus vaccines. In this resubmitted Program Project application, vaccinia virus will be used as a model for orthopoxvirus infection and to study the induction of host immunity. Immune recognition of viruses is in part, regulated by host antigen presenting cells. The overall goal of the program is to elucidate how poxviruses specifically alter the function of these antigen presenting cells, and thus subvert host immunity. A central hypothesis for the program therefore, is that vaccinia virus regulates the function of host antigen presenting cells to diminish the development of adaptive immunity and enhance viral pathogenesis. To address this hypothesis, the program application links three related projects involving a team of highly interactive investigators using complementary, interdisciplinary approaches. Projects within the program address: the specific mechanisms employed by vaccinia virus to modulate class II antigen presentation (Project 1);interplay between host cell signaling pathways and vaccinia virus leading to disruption of CDId-mediated antigen presentation (Project 2);and the importance of lung dendritic cells in regulating respiratory vaccinia virus infection in the context both normal and atopic lung microenvironments (Project 3). These research projects will be supported by an administrative core, and two research facilities including a virus core and a pulmonary biology core, each designed to facilitate studies of viral pathogenesis and host immunity.